268 P.H. Reggio
C-3 side chain of∆^9 -THC ( 1 ) and the morpholino group of 3 with the carbocyclic
ring system of 1. A similar alignment was suggested by Xie et al. (1995) and by Eis-
senstat and co-workers (1995; see above). The C-2 methyl group of 3 was aligned
with the phenolic hydroxyl of 1. Because of the conformational flexibility of 3 ,
these investigators studied the conformational energy of 3 asafunctionofvol-
ume difference with 1. No specific AAI conformation that could be superimposed
with 1 was found to be preferable. Because no specific AAI conformation could be
identified as best to overlay with 1 , these investigators proposed that a unique AAI
pharmacophore may need to be developed. In addition, Dutta et al. proposed that
the keto group of the AAIs may be important for interaction with the CB 1 receptor
(Dutta et al. 1997).
In their initial studies of the AAIs, Huffman and co-workers aligned the carbonyl
oxygen of WIN55,212-2 with the phenolic hydroxyl of∆^9 -THC ( 1 ); the naphthyl
moiety, with the cyclohexyl and pyran ring of 1 ; and the indole nitrogen and the
substituent extending from it with C-3 and its alkyl tail in 1 (Huffman et al. 1994).
Huffman demonstrated that elimination of the AAI naphthyl substituent led to
inactive compounds that failed to bind to the CB 1 receptor (Huffman et al. 1994).
Huffman also showed that the morpholino ring can be replaced by an alkyl side
chain and retain good CB 1 affinity (Huffman et al. 1994).
On the basis of this initial classical CB/AAI alignment, Huffman and co-workers
have synthesized a series of indole- and pyrrole-derived CBs in which the mor-
pholinoethyl group was replaced with another cyclic structure or with a carbon
chainthatmoredirectlycorrespondedtothesidechainof∆^9 -THC ( 1 ). Receptor
affinity and potency of these novel CBs were related to the length of the carbon
chain. Short side chains resulted in inactive compounds, whereas chains with four
to six carbons produced optimal in vitro and in vivo activity. Pyrrole-derived CBs
were consistently less potent than were the corresponding indole derivatives. These
results suggest that, whereas the site of the morpholinoethyl group in these CBs
seems crucial for attachment to CB 1 receptors, the exact structural constraints on
this part of the molecule are not as strict as previously thought (Wiley et al. 1998).